Long-term individual retention with cenobamate in adults with focal seizures: Pooled data from the clinical development program

Objective: We determined retention on open-label cenobamate therapy in the clinical development program to assess the long-term efficacy and tolerability of adjunctive cenobamate in individuals with uncontrolled focal seizures. // Methods: Data from two randomized, controlled cenobamate studies and one open-label safety and pharmacokinetic study were pooled. Based on the percentage of participants remaining on treatment, retention rates were estimated using Kaplan-Meier survival analyses. We performed two additional analyses to assess factors contributing to retention, stratifying a robust data set (through 2 years) by cenobamate modal dose and frequently used concomitant anti-seizure medications. Cenobamate discontinuations and treatment-emergent adverse events were summarized. // Results: Data from 1844 participants were pooled: 149 from a single-dose randomized trial, 355 from a multi-dose randomized trial, and 1340 from an open-label safety and pharmacokinetic study. Most participants from randomized trials continued in open-label extensions, and pooled data represent >95% of participants exposed to cenobamate. Baseline characteristics and disease and treatment histories were similar across studies. Median duration of cenobamate exposure was 34 months, with a median modal dose of 200 mg/day. Kaplan-Meier estimates of cumulative cenobamate retention rates were 80% at 1 year and 72% at 2 years. Once participants reached the maintenance phase, retention rates were consistently high in participants receiving ≥100 mg/day cenobamate, and concomitant anti-seizure medications did not affect long-term retention. By 2 years, 535 (29%) had actually discontinued cenobamate; the most common reasons for discontinuation were adverse events (37.6%), withdrawal of consent (21.1%), and other (16.8%). // Significance: Treatment retention rates provide a proxy measure for long-term efficacy, safety, tolerability, and adherence. The consistently high retention rates we found suggest that cenobamate may be an effective and well-tolerated new treatment option for people with drug-resistant focal seizures

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Uneven focal shoe deterioration in Tourette syndrome.

A 31-year-old single man (AB) sought neuropsychiatric consultation for treatment-resistant motor and vocal tics. He described himself expressing a total of 24 different tics, mainly facial twitches (eye blinking, raising eyebrows, mouth opening, lips licking, stereotyped grimacing) and inappropriate utterances (grunting, throat clearing, sniffing), since the age of 7. There appeared to be no family history of tic disorder. He reported occasional utterance of swear words in contextually inappropriate situations (coprolalia), and the urge to copy other people’s movements (echopraxia). Other tic-associated symptoms included self-injurious behaviours and forced touching of objects. A.B. met both DSM-IV-tr and ICD-10 criteria for Tourette syndrome, and also DSM-IV-tr criteria for attention deficit hyperactivity disorder (combined type) in childhood

The effects of interleukin-8 on airway smooth muscle contraction in cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>Many cystic fibrosis (CF) patients display airway hyperresponsiveness and have symptoms of asthma such as cough, wheezing and reversible airway obstruction. Chronic airway bacterial colonization, associated with neutrophilic inflammation and high levels of interleukin-8 (IL-8) is also a common occurrence in these patients. The aim of this work was to determine the responsiveness of airway smooth muscle to IL-8 in CF patients compared to non-CF individuals.</p> <p>Methods</p> <p>Experiments were conducted on cultured ASM cells harvested from subjects with and without CF (control subjects). Cells from the 2^ndto 5^thpassage were studied. Expression of the IL-8 receptors CXCR1 and CXCR2 was assessed by flow cytometry. The cell response to IL-8 was determined by measuring intracellular calcium concentration ([Ca²⁺]_i), cell contraction, migration and proliferation.</p> <p>Results</p> <p>The IL-8 receptors CXCR1 and CXCR2 were expressed in both non-CF and CF ASM cells to a comparable extent. IL-8 (100 nM) induced a peak Ca²⁺release that was higher in control than in CF cells: 228 ± 7 versus 198 ± 10 nM (p < 0.05). IL-8 induced contraction was greater in CF cells compared to control. Furthermore, IL-8 exposure resulted in greater phosphorylation of myosin light chain (MLC₂₀) in CF than in control cells. In addition, MLC₂₀expression was also increased in CF cells. Exposure to IL-8 induced migration and proliferation of both groups of ASM cells but was not different between CF and non-CF cells.</p> <p>Conclusion</p> <p>ASM cells of CF patients are more contractile to IL-8 than non-CF ASM cells. This enhanced contractility may be due to an increase in the amount of contractile protein MLC₂₀. Higher expression of MLC₂₀by CF cells could contribute to airway hyperresponsiveness to IL-8 in CF patients.</p

The Effect of Climate Fluctuation on Chimpanzee Birth Sex Ratio

Climate and weather conditions, such as the North Atlantic Oscillation, precipitation and temperature influence the birth sex ratio (BSR) of various higher latitude species, including deer, elephant seals or northern human populations. Although, tropical regions show only little variation in temperature, climate and weather conditions can fluctuate with consequences for phenology and food resource availability. Here, we evaluate, whether the BSR of chimpanzees, inhabiting African tropical forests, is affected by climate fluctuations as well. Additionally, we evaluate, if variation in consumption of a key food resource with high nutritional value, Coula edulis nuts, is linked to both climate fluctuations and variation in BSR. We use long-term data from two study groups located in Taï National Park, Côte d'Ivoire to assess the influence of local weather conditions and the global climate driver El Niño Southern Oscillation (ENSO) on offspring sex. Côte d'Ivoire has experienced considerable climate variation over the last decades, with increasing temperature and declining precipitation. For both groups we find very similar time windows around the month of conception, in which offspring sex is well predicted by ENSO, with more males following low ENSO values, corresponding to periods of high rainfall. Furthermore, we find that the time spent cracking and feeding on Coula nuts is strongly influenced by climate conditions. Although, some of our analysis suggest that a higher proportion of males is born after periods with higher nut consumption frequency, we cannot conclude decisively at this point that nut consumption may influence shifts in BSR. All results combined suggest that also chimpanzees may experience climate related shifts in offspring sex ratios as response to climate fluctuation

Restricted-Range Fishes and the Conservation of Brazilian Freshwaters

Background: Freshwaters are the most threatened ecosystems on earth. Although recent assessments provide data on global priority regions for freshwater conservation, local scale priorities remain unknown. Refining the scale of global biodiversity assessments (both at terrestrial and freshwater realms) and translating these into conservation priorities on the ground remains a major challenge to biodiversity science, and depends directly on species occurrence data of high taxonomic and geographic resolution. Brazil harbors the richest freshwater ichthyofauna in the world, but knowledge on endemic areas and conservation in Brazilian rivers is still scarce. Methodology/Principal Findings: Using data on environmental threats and revised species distribution data we detect and delineate 540 small watershed areas harboring 819 restricted-range fishes in Brazil. Many of these areas are already highly threatened, as 159 (29%) watersheds have lost more than 70% of their original vegetation cover, and only 141 (26%) show significant overlap with formally protected areas or indigenous lands. We detected 220 (40%) critical watersheds overlapping hydroelectric dams or showing both poor formal protection and widespread habitat loss; these sites harbor 344 endemic fish species that may face extinction if no conservation action is in place in the near future. Conclusions/Significance: We provide the first analysis of site-scale conservation priorities in the richest freshwater ecosystems of the globe. Our results corroborate the hypothesis that freshwater biodiversity has been neglected in former conservation assessments. The study provides a simple and straightforward method for detecting freshwater priority areas based on endemism and threat, and represents a starting point for integrating freshwater and terrestrial conservation in representative and biogeographically consistent site-scale conservation strategies, that may be scaled-up following naturally linked drainage systems. Proper management (e. g. forestry code enforcement, landscape planning) and conservation (e. g. formal protection) of the 540 watersheds detected herein will be decisive in avoiding species extinction in the richest aquatic ecosystems on the planet.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Gordon and Betty Moore Foundatio

Aerosolized Human Extracellular Superoxide Dismutase Prevents Hyperoxia-Induced Lung Injury

An important issue in critical care medicine is the identification of ways to protect the lungs from oxygen toxicity and reduce systemic oxidative stress in conditions requiring mechanical ventilation and high levels of oxygen. One way to prevent oxygen toxicity is to augment antioxidant enzyme activity in the respiratory system. The current study investigated the ability of aerosolized extracellular superoxide dismutase (EC-SOD) to protect the lungs from hyperoxic injury. Recombinant human EC-SOD (rhEC-SOD) was produced from a synthetic cassette constructed in the methylotrophic yeast Pichia pastoris. Female CD-1 mice were exposed in hyperoxia (FiO2>95%) to induce lung injury. The therapeutic effects of EC-SOD and copper-zinc SOD (CuZn-SOD) via an aerosol delivery system for lung injury and systemic oxidative stress at 24, 48, 72 and 96 h of hyperoxia were measured by bronchoalveolar lavage, wet/dry ratio, lung histology, and 8-oxo-2′-deoxyguanosine (8-oxo-dG) in lung and liver tissues. After exposure to hyperoxia, the wet/dry weight ratio remained stable before day 2 but increased significantly after day 3. The levels of oxidative biomarker 8-oxo-dG in the lung and liver were significantly decreased on day 2 (P<0.01) but the marker in the liver increased abruptly after day 3 of hyperoxia when the mortality increased. Treatment with aerosolized rhEC-SOD increased the survival rate at day 3 under hyperoxia to 95.8%, which was significantly higher than that of the control group (57.1%), albumin treated group (33.3%), and CuZn-SOD treated group (75%). The protective effects of EC-SOD against hyperoxia were further confirmed by reduced lung edema and systemic oxidative stress. Aerosolized EC-SOD protected mice against oxygen toxicity and reduced mortality in a hyperoxic model. The results encourage the use of an aerosol therapy with EC-SOD in intensive care units to reduce oxidative injury in patients with severe hypoxemic respiratory failure, including acute respiratory distress syndrome (ARDS)

Induction of beta defensin 2 by NTHi requires TLR2 mediated MyD88 and IRAK-TRAF6-p38MAPK signaling pathway in human middle ear epithelial cells

<p>Abstract</p> <p>Background</p> <p>All mucosal epithelia, including those of the tubotympanium, are secreting a variety of antimicrobial innate immune molecules (AIIMs). In our previous study, we showed the bactericidal/bacteriostatic functions of AIIMs against various otitis media pathogens. Among the AIIMs, human β-defensin 2 is the most potent molecule and is inducible by exposure to inflammatory stimuli such as bacterial components or proinflammatory cytokines. Even though the β-defensin 2 is an important AIIM, the induction mechanism of this molecule has not been clearly established. We believe that this report is the first attempt to elucidate NTHi induced β-defensin expression in airway mucosa, which includes the middle ear.</p> <p>Methods</p> <p>Monoclonal antibody blocking method was employed in monitoring the TLR-dependent NTHi response. Two gene knock down methods – dominant negative (DN) plasmid and small interfering RNA (siRNA) – were employed to detect and confirm the involvement of several key genes in the signaling cascade resulting from the NTHi stimulated β-defensin 2 expression in human middle ear epithelial cell (HMEEC-1). The student's <it>t</it>-test was used for the statistical analysis of the data.</p> <p>Results</p> <p>The experimental results showed that the major NTHi-specific receptor in HMEEC-1 is the Toll-like receptor 2 (TLR2). Furthermore, recognition of NTHi component(s)/ligand(s) by TLR2, activated the Toll/IL-1 receptor (TIR)-MyD88-IRAK1-TRAF6-MKK3/6-p38 MAPK signal transduction pathway, ultimately leading to the induction of β-defensin 2.</p> <p>Conclusion</p> <p>This study found that the induction of β-defensin 2 is highest in whole cell lysate (WCL) preparations of NTHi, suggesting that the ligand(s) responsible for this up-regulation may be soluble macromolecule(s). We also found that this induction takes place through the TLR2 dependent MyD88-IRAK1-TRAF6-p38 MAPK pathway, with the primary response occurring within the first hour of stimulation. In combination with our previous studies showing that IL-1α-induced β-defensin 2 expression takes place through a MyD88-independent Raf-MEK1/2-ERK MAPK pathway, we found that both signaling cascades act synergistically to up-regulate β-defensin 2 levels. We propose that this confers an essential evolutionary advantage to the cells in coping with infections and may serve to amplify the innate immune response through paracrine signaling.</p